MANAGING APLA - AN EVIDENCE BASED PRACTICAL APPROACH BY DR SHASHWAT JANI

MANAGING APLA - AN EVIDENCE BASED PRACTICAL APPROACH BY DR SHASHWAT JANI

1. Managing A. P. L. A.

( An Evidence Based Practical Approach )
Dr. Shashwat Jani
M. S. ( Obs – Gyn ), F.I.A.O.G.
Diploma in Advance Laparoscopy.
Consultant Assistant Professor,
Smt. N.H.L. Municipal Medical College.
Sheth V. S. General Hospital , Ahmedabad.
Mobile : [phone].
E-mail : [email protected]

2. APS
Antiphospholipid syndrome
(APS) is a systemic autoimmune
disorder characterized by venous or
arterial thrombosis and/or
pregnancy loss in the presence of
persistent antiphospholipid
antibodies (aPL).
22-May-18
Dr Shashwat Jani.
[phone].
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3.  Antiphospholipid syndrome (Hughes
syndrome) is a disorder of immune system ,
characterized by excessive clotting of blood ,
thrombocytopenia & /or adverse pregnancy
outcomes.
 Body recognizes negatively charged
phospholipids on cell membrane as foreign &
produces antibodies against them leading to an
acquired autoimmune thrombophilia.
Antiphospholipid ( APLA )
syndrome

4. Antiphospholipid Antibody syndrome (APLA)
•Primary antiphospholipid syndrome (PAPS) - when APS
occurs in the absence of any other related disease (LA,
ACL antibodies in patient’s serum).
•Secondary antiphospholipid syndrome - when APS
coexists with other diseases such as SLE I
• In catastrophic APLA (rare ), APS leads to rapid organ
failure due to generalised thrombosis & a high risk of
death
•Other rare antibodies to phosphotidyl ethanolamine &
phosphotidylserine are also associated with it.

5. Epidemiology

•General population: 2-4%. increases with
age and chronic disease
•Recurrent fetal loss: 15 %
•SLE: 30%
•aCL antibodies: more common than LA
(aCL 5X more than LA) .
22-May-18
Dr Shashwat Jani.
[phone].
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6. APLA & Infertility
•Controvertial.
•aPl is responsible for implantation failure. aPL
is 23% in females referred for IVF Vs 2% in
fertile females .
(Chilcott et al,2000)
•Routine screening for aPL among women
undergoing IVF-ET is not warranted.
(Branch et al,2003)

22-May-18
Dr Shashwat Jani.
[phone].
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7. APLA & Pregnancy

1. Recurrent pregnancy loss. 25%.
Majority: in 1st T after the establishment of FHR
activity.
15% of RPL
2. Preeclampsia: 15-50%.
15% of severe PET before 34 wks have APL Ab
3. IUGR: 30%
4. Preterm labor
5. Maternal thrombosis (including strokes)
22-May-18
Dr Shashwat Jani.
[phone].
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8. Mechanisms
1. Inhibition of trophoblastic function&
differentiation (Bose et al, 2005)
2. Activation of complement pathways at the
maternal–fetal interface: local inflammatory
response (Salmon et al, 2003)
3. In later pregnancy, thrombosis of the
uteroplacental vasculature (Peaceman et al, 1993).
neither universal nor specific (Jivraj & Rai, 2003)

22-May-18
Dr Shashwat Jani.
[phone].
8

9. APLA IN
POSTPARTUM PERIOD
Postpartum syndrome
This is a rare syndrome characterised by
pleuropulmonary disease, fevers and cardiac
manifestations.9 The mechanism is unknown,
•although extensive immunoglobulin IgG, IgM,
•IgA and C3 deposition in the myocardium has
•been reported.
22-May-18
Dr Shashwat Jani.
[phone].
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10. Diagnosis
22-May-18
Dr Shashwat Jani.
[phone].
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11. International consensus conference
held in Sapporo (1998).
22-May-18
Dr Shashwat Jani.
[phone].
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12. 22-May-18
Dr Shashwat Jani.
[phone].
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13. Amendments to the
Sapporo criteria :
• More insights into clinical, laboratory,
and experimental criteria.
• No clear cutoffs for “medium to high
titers” of IgG and IgM anticardiolipin
(aCL).
• Timing of laboratory testing in
relation to the clinical event was not
clarified.
22-May-18
Dr Shashwat Jani.
[phone].
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14. 22-May-18
Dr Shashwat Jani.
[phone].
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15. 22-May-18
Dr Shashwat Jani.
[phone].
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16. Advancement In
Sydney Clinical Criteria For APS
(2006)
 Better definition of clinical criteria.
 Stratification of patients as per primary or secondary
APS.
 Time interval increased to 12 weeks.
 Transient positivity excluded.
 Categorization of asymptomatic aPL and
Catastrophic APS ( CAPS ).
 APS with or without associated rheumatic disease.
22-May-18
Dr Shashwat Jani.
[phone].
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17. Interpretation
• A repeat tests at least 12 Wks apart.
{Individuals may have transiently positive test
because a low to mid positive level can be due to
viral illness and revert to normal & those with an
initial negative test may be in the transient negative
phase of their aPL cycle.}
• LA, aCL and aβ2GPI testing are all required for
the accurate diagnosis .
• Once APS is diagnosed, serial aPL testing is not
useful .

22-May-18
Dr Shashwat Jani.
[phone].
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18. “NON CRITERIA “ – APS Findings
Thrombocytopenia and/or hemolytic anemia.
Transverse myelopathy or myelitis.
Livido reticularis.
Cardiac valve disease.
Nephropathy.
Non-thrombotic neurologic manifestations,
including multiple sclerosis - like syndrome,
chorea, or migraine headaches.
Miyakis, et al., J.Thromb.Haemost., 2006; 4: 295-306
22-May-18
Dr Shashwat Jani.
[phone].
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19. Indications for testing for APLA
Obstetric indications:
1.Unexplained stillbirth
2.Recurrent pregnancy loss
3.Unexplained 2nd or 3rd T fetal death
4.IUGR
5.Severe preeclampsia at less than 34 wks
6.Placental abruption (previous or current)
22-May-18
Dr Shashwat Jani.
[phone].
19

20. Non-obstetric indication :
1.False positive serologic test for syphilis
2.Autoimmune diseases: SLE,
thrombocytopenia
3. Unexplained thrombosis
4. Haemolytic anaemia
5. Stroke, especially between 25-50 yr
6. Livedo reticularis
22-May-18
Dr Shashwat Jani.
[phone].
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21. Investigation Plan
If APS suspected - as per the laboratory
diagnostic criteria following aPL are tested :

 Lupus anti coagulant (LA/LAC)
 Anticardiolipin antibody (aCL).
 Anti beta 2 GP-1 (β2GP- 1)
22-May-18
Dr Shashwat Jani.
[phone].
21

22. Lupus Anticoagulant (LAC)
•Misnomer - associated with hypercoagulable
state and frequently found in patient without SLE.
•An immunoglobulin (IgG / IgM/ Both) – interfere
with one or more phospholipid-dependent test of
in vitro coagulation.
Most common test that identify LAC includes
•aPTT- activated partial thromboplastin time
•KCT - the kaolin clot time test
•dRVVT- dilute Russell viper venom time
•PCT - plasma clot time.
22-May-18
Dr Shashwat Jani.
[phone].
22

23. 22-May-18
Dr Shashwat Jani.
[phone].
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24. Anticardio Lipin Antibody
•Cardiolipin (phospholipid) – on membrane.
•ELISA –gold standard.
•IgG,IgM,and IgA-Standard sera available.
•Ability to bind 1 ug of cardiolipin and result in
titres.
•Value decline in pregnancy as increase in plasma
volume causes dilution of phospholipid.
22-May-18
Dr Shashwat Jani.
[phone].
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25. 22-May-18
Dr Shashwat Jani.
[phone].
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26. Management
22-May-18
Dr Shashwat Jani.
[phone].
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27. Aim Of Management
1. To maximize the chance of successful
fetal outcome.
2. To prevent thrombosis and other clinical
manifestations of APS in the mother.
3. To ensure good counseling and planning
for future pregnancies.
22-May-18
Dr Shashwat Jani.
[phone].
27

28. Prepregnancy Planning
1. Clinical: Review medical and obstetric history
2. Laboratory:
(a) document and confirm persistent antiphospholipid
antibodies
(b) assess renal function
(c) assess full blood count for presence of thrombocytopenia
and/or anaemia
(d) antibody testing: lupus anticoagulant, aCL, anti-2GPI, anti-
Ro and La antibodies (even if there is no evidence of SLE:
•these antibodies are associated with a 2% risk of complete
heart block in the fetus and up to a 5% risk of neonatal lupus).
22-May-18
Dr Shashwat Jani.
[phone].
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29. 22-May-18
Dr Shashwat Jani.
[phone].
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3 ) Treatment Prepregnancy:
(a) Optimise the woman's clinical state and
pharmacological treatment
(b) Postpone pregnancy if a thrombotic event has
occurred within the last 6 months
(c) Postpone if SLE has been active or hypertensive
(d) Assess individual additional risk factors such as
obesity and maternal age
(f) Ensure that the plan is understood, e.g.
substituting heparin for warfarin at the time of the
first missed period

30. Remember
 With no treatment - only 20-30% of
patient with aPL antibody has successful
delivery.
 Combination of unfractionated heparin
with low dose aspirin provide the highest
success rate in terms of live birth.
 Low dose heparin with low dose aspirin
reduces the pregnancy loss by 54%.
22-May-18
Dr Shashwat Jani.
[phone].
30

31. • Low dose aspirin 75 mg should be
initiated before conception and
discontinued 4 weeks before EDD.

M.O.A of Aspirin –
Selective inhibition of thromboxane
production - Restoration of balance with
prostaglandin.
22-May-18
Dr Shashwat Jani.
[phone].
31

32. IVF in APS
 IVF is potentially dangerous since ovulation
induction regimens trigger an estrogen-induced
hypercoagulable state.
 If performed, women with a history of
thrombosis-associated APS should be switched
from their usual oral anticoagulant to
therapeutic dose unfractionated heparin, which
should be maintained after oocyte retrieval.
 If the patient conceives, she should be
switched to LMWH.
22-May-18
Dr Shashwat Jani.
[phone].
32

33. Antepartum Surveillance
• If h/o first trimester losses - do USG weekly till
progress beyond the point of their prior losses.
• If h/o second / third trimester fetal loss – Serial
antepartum testing required.
Close fetal surveillance needed in form of 30-32 wk
onwards …
 Nonstress test - twice weekly.
 Biophysical profile weekly.
 Daily fetal kick count,
22-May-18
Dr Shashwat Jani.
[phone].
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34. 22-May-18
Dr Shashwat Jani.
[phone].
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35. ANTICOAGULATION
THERAPY
•Heparin should be continued until the
onset of spontaneous labor Or night
before scheduled induction/operative
delivery.
•If the patient is fully anticoagulated and
delivery is emergent -
1% Protamine sulphate , iv over 10 min.
22-May-18
Dr Shashwat Jani.
[phone].
35

36. After confirmation of pregnancy.
 5000 units every 12 hr.-
 Platelets and PTT –
•base line
•every week for 2 weeks
•Once in each trimester throughout pregnancy .
22-May-18
Dr Shashwat Jani.
[phone].
36

37. With prior h/o thromboembolism –
•Therapeutic dose required 10000-12000 IU
sc/day.
•Does not cross the placenta
•Aim to keep aPTT at the upper end of normal
range.
22-May-18
Dr Shashwat Jani.
[phone].
37

38. Side effect of Heparin
Heparin induced thrombocytopenia (HIT)-

•Incidence 1% at dose >15000Iu/day(combined
with low platelets in pregnancy.)
•Bleeding risks - If platelets counts decreases
significantly , heparin dosage should be reduced.
•Splenectomy -- early second trimester or at the
time of CS may be considered in patients with
thrombocytopenia refractory to glucocorticoid
therapy.
22-May-18
Dr Shashwat Jani.
[phone].
38

39. Heparin induced osteopenia –
•Dose > 15000 IU/day (combined with normal
osteoporosis associated with pregnancy .
•Heparin-induced osteoporosis occurs in 1-2%
of cases risks of osteopenia.
•Bone density studies should be considered.
•Warfarin may be substituted for heparin
during the postpartum period to limit further
risk of heparin induced osteoporosis and bone
fracture

22-May-18
Dr Shashwat Jani.
[phone].
39

40. UFH Vs LMWH
•LMWH - have therapeutic effect with less side effect.
•LMWH - Single daily dose.
•Prophylactic LMWH-
Enoxaparin - 40mg s/c once/day
Dalteparin - 5000u s/c once/day
•Therapeutic LMWH-
Enoxaparin-1mg/kg/12 hr
Dalteparin-200u/kg once daily.
•Prophylactic UFH - 5000 u s/c every 12 hr.
•Therapeutic UFH - 10,000 u s/c every 12 hr.
22-May-18
Dr Shashwat Jani.
[phone].
40

41. Calcium & Vit. D
The heparinised pregnant patient
• increase her calcium to 600 mg BD
• Along with vitamin D to optimise the
absorption of calcium and reduce the risk of
osteopenia.
22-May-18
Dr Shashwat Jani.
[phone].
41

42. Delivery Plan
•Elective termination of pregnancy at term.
•Caesarean delivery associated with higher rate
of peripartum thrombosis.
•Vaginal delivery is preferred.
Obs gynecol clin N Am 2007
•Epidural anesthesia is not recommended in
marked drop in the maternal platelet count.
22-May-18
Dr Shashwat Jani.
[phone].
42

43. Post Partum Surveillance
•Post vaginal delivery - Ambulation as soon as
possible.
•Post cesarean delivery - Pneumatic compression
stocking untill ambulation.
•Aspirin low dose –reinitiated.
•Heparin should be restarted post partum at
lowest pre delivery dosage – continue for 4-6
week.
•In pt. With thromboembolic events - full
anticoagulant - 6 wk.
22-May-18
Dr Shashwat Jani.
[phone].
43

44. • Supplemental calcium to be continued as
long as pt is on heparin.
•No evidence indicates adverse effects related
to breastfeeding with low dose aspirin and
heparin.
•Breastfeeding is not recommended if high
doses of cytotoxic or immunosuppressive
agents are required . (secondary APS)
22-May-18
Dr Shashwat Jani.
[phone].
44

45. Follow Up
•Once the diagnosis - diagnosis for life long.
(inspite of resolution).
•Inform about potential maternal and obstetric
problems.
•Consultation with specialists in Maternal-Fetal
Medicine and Rheumatology .
• APS and 1 or more prior thrombotic events,
lifelong anticoagulation with warfarin - to avoid
recurrent thrombosis.
22-May-18
Dr Shashwat Jani.
[phone].
45

46. Life style modification
•Maintain a normal weight.
•Increased cholesterol – correction.
•Avoid tobbaco related product.
•Lifelong aspirin (low dose) /day - should be
continued.
22-May-18
Dr Shashwat Jani.
[phone].
46

47. Contraception
•Estrogen containing oral
contraceptives should be avoided
in repeated positive aPL.
•Progesterone only pills, barrier
method, IUD can be used.
22-May-18
Dr Shashwat Jani.
[phone].
47

48. Other Drugs Used In Pregnancy
•Previously Prednisolone was used –
No benefit as per trial.
•IVIG and HCQ ( Hydroxychloroquine ) – pt.
With failed treatment with heparin.
•Warfarin only after organogenesis is complete.
(pauzner et al)
22-May-18
Dr Shashwat Jani.
[phone].
48

49. New Drugs
Rituximab
•Helpful in treating low platelets , anemia
small vessel clots
Eculizumab
•In refractory APS - under evaluation.

22-May-18
Dr Shashwat Jani.
[phone].
49

50. Future
More specific , targeted , immunomodulatory
approach in the future.
Specific compliment inhibitor for pregnancy
complication.
Long term follow up of children born to APS
mother.
Autologous Hematopoietic Stem Cell
Transplantation (HSCT).
22-May-18
Dr Shashwat Jani.
[phone].
50

51. Recommendations
 Women with recurrent pregnancy loss
before 10 weeks gestation should be screened
for aPL.
 For women with APS with recurrent
pregnancy loss, antenatal administration of
heparin combined with low dose aspirin is
recommended throughout pregnancy .
 Treatment should begin as soon as
pregnancy is confirmed.
22-May-18
Dr Shashwat Jani.
[phone].
51

52.  For women with APS and a
history of preeclampsia or FGR, low
dose aspirin is recommended.
 Women with aPL should be
considered for post-partum
thromboprophylaxis.
22-May-18
Dr Shashwat Jani.
[phone].
52

53. Take Home Message
Be APS minded :
It is a correctable cause of RPL, so one has to
be APS minded in patients presenting with
pregnancy morbidity.
Identify The At Risk Women :
To identify the at risk women and screen
out patient who warrant thromboprophylaxis and
thus we can prevent potentially life threatening
complications of thrombosis.
22-May-18
Dr Shashwat Jani.
[phone].
53